The Involvement Of The Signal-transducing Function Of Na～+, K～+-ATPase In The Mechanism Of The Positive Inotropic Effect Of Strophanthidin

Cardiotonic steroid (Cs) had been used for the congestive heart failure (CHF) for more than 200 years. But the mechanism of its positive inotropic effect is still controversial. It is generally believed that Cs produce positive inotropic actions in failure heart via inhibition of Na⁺, K⁺-ATPase activities which leads to an increase in intracellular Na+ concentration ([Na⁺]_i), and in turn raises intracellular Ca²⁺ concentration ([Ca²⁺]_i ) via Na⁺-Ca²⁺ exchange, thus increasing the uptake and subsequent release of Ca²⁺ by the sarcoplasmic reticulum (SR).Recently, many studies show that in addition to pumping ions, Na⁺-K⁺–ATPase in the plasma membrame acts also as signal transducer. Na⁺-K⁺–ATPase interacts with neighboring membrane proteins and organizes cytosolic cascades of signaling proteins from the plasma to the nucleus and regulates cell growth and gene expression.Up to days, in cardiac myocytes, binding of Cs to Na⁺-K⁺–ATPase results in activation of two main signal transduction pathways. One is Cs / Na⁺-K⁺–ATPase / Src/EGFR/Ras/ROS cascade (ROS pathway). The other is Cs / Na⁺-K⁺–ATPase / Src/EGFR / Ras / P42/44 MAPK cascade (MAPK pathway). So Na⁺-K⁺–ATPase regulates cell growth and gene expression and increases in intracellular Ca²⁺ through these two signal transduction pathways. ROS and the intracellular Ca²⁺ are essential second messagers. In addition, p42/44 MAPK can open the L-type Ca²⁺ channel to make the connection between the long-term regrulation of cell growth and the short-term increase in intracellular Ca²⁺. So whether does signal-transducing function of Na⁺, K⁺-ATPase that increases intracellular Ca²⁺ involve in the mediating the positive inotropic actions?Recently, Xie et al reported that, in neonatal and adult rat cardiac...